Ezetimibe is in a class of compounds known as lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol and related phytosterols. Its chemical name is as (3R,4S)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one and has a chemical structure which is shown in the Formula 1.

Ezetimibe reduces blood cholesterol by inhibiting the absorption of cholesterol by the small intestine. Its mechanism of action differs from those of other classes of cholesterol-reducing compounds, such as HMG-CoA reductase inhibitors. It doesn't inhibit cholesterol synthesis in the liver, or increase bile acid excretion but inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. Such mechanism is complementary to that of HMG-CoA reductase inhibitors.
Ezetimibe is marketed under the brand name ZETIA® or EZETROL®, which is available as a tablet for oral administration containing 10 mg of ezetimibe and the following inactive ingredients: croscarmellose sodium, lactose monohydrate, microcrystalline cellulose, povidone, sodium lauryl sulphate and magnesium stearate.
In prior art, there are many patents including ezetimibe in several different pharmaceutical compositions, for example ezetimibe is identified by the structural formula which is disclosed in EP patent, EP 0720599 B1 (Schering Corporation) 21.09.1993. Another EP patent EP 1353696 B1 (Schering Corporation) 26.01.2001 discloses the pharmaceutical formulation containing ezetimibe, lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, sodium lauryl sulfate and magnesium stearate
EP application, EP 1849459 A1 (Teva Pharmaceutical Ind. Ltd.) 06.03.2006, encompasses an ezetimibe composition comprising ezetimibe co-milled with at least one hydrophilic excipient such as saccharide or polysaccharide (e.g. starch). The ezetimibe composition further contains magnesium stearate, microcrystalline cellulose and povidone (page 6, ex. 2). Co-milled ezetimibe has a particle size d (0.5) less than or equal to about 5 μm and d(0.9) less than or equal to about 20 μm, (page 3, paragraph 22). In this invention, about 40% to about 70% ezetimibe composition is dissolved in 20 minutes, and about 50% or more of the ezetimibe composition is dissolved in 40 minutes, (page 3, paragraph 21).
US application US 2007/0275052 A1 (Glenmark Pharmaceuticals Ltd.) 24.05.2006, also discloses the pharmaceutical composition comprising micronized ezetimibe of which about 90% of the particles are not more than about 7 microns and of which about 50% of the particles are not more than about 4 microns (page 1-2, paragraph 18). In this invention one of the pharmaceutical formulations contains ezetimibe, lactose monohydrate, crospovidone, povidone and magnesium stearate (page 2, ex. 1) and other pharmaceutical formulation contains ezetimibe, lactose monohydrate, sodium starch glycolate, sodium lauryl sulphate, povidone and magnesium stearate (page 2, ex. 2). PCT application WO 2008/101723 A2 (Krka) 23.02.2007, relates to a pharmaceutical composition comprising at least one cholesterol absorbtion inhibitor such as ezetimibe in amorphous form and at least one hydrophilic polymer.
Ezetimibe is reported as practically insoluble in water, which cause it to exhibit a low dissolution rate in aqueous media such as gastrointestinal fluids, which can result in low bioavailability after oral ingestion.
In prior art, it is known that for improving bioavailability, particle size reduction is used for water-insoluble drugs. However, particle size reduction is not always effective enough for increasing the dissolution rate of a drug to a certain required value. Many water-insoluble drugs have a strong tendency to agglomerate into larger particles with an overall decrease in effective surface area during the manufacturing process. Further it has been reported that extremely small sizes (less than 10 μm) may be inadvisable for some drug substances. (A. R. Gennaro, Remington's Pharmaceutical Sciences, 18th ed., pages 591, 1436-1437). The technical problem of particle size reduction may occur during the manufacturing and tabletting procedure such as agglomeration and bad flowabilty because of having less glidant and lubricant characteristics of drug substances in powder form.
As shown above many different approaches how to improve bioavailability of low soluble drugs have been disclosed in the prior art. Therefore, there is a need in the art to provide improved pharmaceutical compositions of ezetimibe that overcome the problems of the prior art with having high bioavailability with improved solubility and dissolution rate which is stable throughout the shelflife, commercially cost low and plant-friendly manufacturing process.